1. Field of the Invention
This invention relates generally to sleep inducing compounds, as well as to methods for induction of sleep by administration of one or more of such compounds to an animal in need thereof.
2. Description of the Related Art
Most people experience, at least transiently and often chronically, problems with sleep. Insomnia occurs at all ages with half of all adults in the United States affected at times (The Gallup Organization, Sleep in America: A National Survey of U.S. Adults, The National Sleep Foundation, Washington, D.C., 1995). Insomnia compromises feelings of wellbeing and judgment and performance at tasks requiring alertness (Gillin, Postgrad Med. 1992; 92: 157-160). Significantly, inadequate sleep correlates with increased morbidity and mortality (Zammit et al, Sleep 1999; 22: S379-85).
In a clinical setting, insomnia may be classified as transient, short-term, or chronic, with durations of a few days, a few weeks, or long-term, respectively (Chessor, Sleep 2000; 22: 237-41). Common etiologies for transient insomnia include acute illness, social stress, jet lag, and work shift changes. Short-term insomnias can be caused by grief, stress, and substance exposure. Chronic insomnias can be associated with underlying disease, depression, psychophysiologic conditions, chronic stress, bereavement, substance exposure, and a variety of primary sleep disorders including sleep apnea, periodic limb movement disorder, restless leg syndrome, narcolepsy and hypersomnia. The primary task of the physician is to identify the specific etiology of the insomnia and prescribe a causally specific therapeutic intervention (Pary et al, Postgrad Med. 1996; 100: 195-210).
The categories of drugs used as sedative-hypnotics in the United States (Wang et al., Drug Disposition and Pharmacokinetics 2003; 37: 10-29) include barbiturates, the benzodiazepine hypnotics, benzodiazepine nonhypnotics, benzodiazepine receptor agonists, antidepressants, antipsychotics, miscellaneous compounds including chloral hydrate, and the antihistamines.
With regard to the antihistamines, histamine enjoys a variety of important chemical messenger roles, having activity toward at least four histamine receptors (i.e., H1-H4) and regulatory function in the nervous, gastrointestinal and immune systems. The antihistamines are reversible competitive ligands of the histamine H1 receptor, and have been categorized over the years as first-, second-, or third-generation classes differentiated by chemical structure and refinement of action. Specifically, first-generation antihistamines such as diphenhydramine, chlorpheniramine, clemastine, hydroxyzine and triprolidine provide H1 receptor blockade, but have significant side effects including sedation, CNS dysfunction due to leakage into the CNS, and anticholinergic adverse effects. In response, the second-generation or so-called “nonsedating” antihistamines, including astemizole, terfenadine, loratadine, cetirizine and fexofenadine, were developed. These compounds have reduced CNS impact and additional antiallergic properties, including inhibition of mast cell degranulation. Desloratadine, a metabolite of loratadine, has been categorized as a third-generation antihistamine (McClellan & Jarvis, Drugs 2001; 61: 789-796), and has direct effects on inflammatory mediators such as inhibition of intracellular adhesion molecule-1 (ICAM-1) expression by nasal epithelium. The importance of histamine in sleep regulation is evidenced by the hypnotic effects of certain histamine receptor ligands (Mignot et al., Nature Neuroscience Supplement; 5: 1071-1075), particularly the older generation molecules.
While significant advances have been made in the field of sleep initiation and prolongation, there continues to be a need in the art for compounds that are effective as sedative and hypnotic agents, especially for compounds with clinical application to the treatment of insomnia. In particular, there remains a need for compounds having improved selectivity, a quicker onset of action, a shorter half-life and/or the ability to penetrate the CNS. The present invention fulfills these needs and other needs, and provides further related advantages.